6EL6

Glucocorticoid Receptor in complex with compound 4

Summary for 6EL6

• Entry DOI: 10.2210/pdb6el6/pdb
• Descriptor: Glucocorticoid receptor, Nuclear receptor coactivator 2, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: glucocorticoid receptor, nuclear hormone receptor, steroid receptor, ligand complex, peptide complex, signaling protein
• Biological source: Homo sapiens (Human); More
• Cellular location: Isoform Alpha: Cytoplasm . Isoform Beta: Nucleus . Isoform Alpha-B: Nucleus : P04150; Nucleus: Q15596
• Total number of polymer chains: 2
• Total formula weight: 34418.64

Authors

Edman, K.,Wissler, L. (deposition date: 2017-09-28, release date: 2018-02-21, Last modification date: 2024-01-17)

Primary citation

Ripa, L.,Edman, K.,Dearman, M.,Edenro, G.,Hendrickx, R.,Ullah, V.,Chang, H.F.,Lepisto, M.,Chapman, D.,Geschwindner, S.,Wissler, L.,Svanberg, P.,Lawitz, K.,Malmberg, J.,Nikitidis, A.,Olsson, R.I.,Bird, J.,Llinas, A.,Hegelund-Myrback, T.,Berger, M.,Thorne, P.,Harrison, R.,Kohler, C.,Drmota, T.
Discovery of a Novel Oral Glucocorticoid Receptor Modulator (AZD9567) with Improved Side Effect Profile.
J. Med. Chem., 61:1785-1799, 2018

PubMed Abstract: Synthetic glucocorticoids (GC) are essential for the treatment of a broad range of inflammatory diseases. However, their use is limited by target related adverse effects on, e.g., glucose homeostasis and bone metabolism. Starting from a nonsteroidal GR ligand (4) that is a full agonist in reporter gene assays, we exploited key functional triggers within the receptor, generating a range of structurally diverse partial agonists. Of these, only a narrow subset exhibited full anti-inflammatory efficacy and a significantly reduced impact on adverse effect markers in human cell assays compared to prednisolone. This led to the discovery of AZD9567 (15) with excellent in vivo efficacy when dosed orally in a rat model of joint inflammation. Compound 15 is currently being evaluated in clinical trials comparing the efficacy and side effect markers with those of prednisolone.

PubMed: 29424542
DOI: 10.1021/acs.jmedchem.7b01690

Experimental method

X-RAY DIFFRACTION (2.4 Å)